Age-related osteoporotic fractures are largely due to an increased propensity to fall and an increase in bone fragility due to a reduction in bone strength with aging. Several factors contribute to bone strength including bone mineral density (BMD), bone structure, bone quality and bone turnover, all four of which have phenotypes that are highly heritable. The long-term goal of this application is to identify genes that underlie bone fragility using the positional cloning/candidate approach. The first step to attaining this goal is to identify chromosomal regions that harbor genes that affect the components of bone fragility and predisposition to fracture. Identification of these genes may: 1) lead to molecular tests that predict the risk of osteoporosis, thereby allowing the early institution of preventive measures; 2) provide insight into the basic skeletal biology that underlies bone fragility and the predisposition to fracture; and 3) identify molecular targets for the development of therapeutic agents aimed at increasing bone strength.